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Histones Play Role in Sepsis

In a surprising finding, histones, which help pack DNA into
chromosomes, were tied to the life-threatening illness sepsis.
The proteins are now potential molecular targets for treating
sepsis and other inflammatory diseases.

Histones help organize long DNA strands into tightly-packed
chromosomes.

Sepsis is a caused by the body's immune system going into overdrive,
usually because of an infection. It causes inflammation and small
blood clots, blocking blood flow to vital organs and leading
to organ failure. A quick diagnosis is crucial, because 1 of
every 3 people who get sepsis die from it.

A synthetic form of activated protein C (APC), which inhibits
clots and inflammation in the human body, is the only drug approved
by the U.S. Food and Drug Administration for treating severe
sepsis. With the hope of gaining insight into designing more
effective treatments for sepsis, a team led by Dr. Charles Esmon
at the Oklahoma Medical Research Foundation set out to gain a
better understanding of how APC works. The investigation was
funded by NIH's National Institute of General Medical Sciences
(NIGMS), the Howard Hughes Medical Institute and the University
of Bari, Italy.

The team began by examining proteins in cell cultures that
had been treated with APC. As reported online on October 25,
2009, in Nature Medicine, APC treatment caused 3 new
bands to appear on protein gels. Sequencing of the proteins revealed
that they were portions of histones. Histones are the structural
supports around which long DNA strands are wound to make a more
compact shape.

The researchers confirmed that APC cleaves histones. They also
found that, while adding histones to cell cultures causes extensive
cell damage, APC helps protect the cells. These experiments implied
that APC may protect against sepsis, at least in part, by cleaving
histones. To test the idea, the researchers turned to some frozen
baboon blood plasma.

Years ago, Esmon's team worked on the development of APC to
treat sepsis, using baboons to study APC's effects. The animals
had been rescued with APC after receiving lethal levels of the
bacteria E. coli to produce septic shock. When the researchers
examined the frozen blood samples collected during those experiments,
they found higher levels of histones during septic shock and
cleaved histones in baboons treated with APC. They also detected
cleaved histones in samples from at least 1 human treated with
APC.

The researchers directly tested whether histones play a role
in sepsis by injecting histones into mice to cause lethal sepsis.
APC rescued mice given a lethal dose of histones, as did an antibody
that bound to histones.

During a serious infection, cells are damaged, causing histones
to be released into the blood stream. "People had seen histones
out in the circulation before and they'd say, 'So what?' But
it wasn't so what. These guys are really bad players," Esmon
says.

The researchers plan to look for histones in the blood of patients
with autoimmune disease such as lupus or type 1 diabetes, as
well as any disease with major complications in blood vessels,
such as myocardial infarction and reperfusion injuries. A drug
that could block histones may have promise for more than septic
shock patients.